Pemetrexed for the treatment of non-small-cell lung cancer (appraisal consultation document)
Appraisal Consultation Document
Background
Key dates
Appraisal Committee's preliminary recommendations
The technology
The manufacturer's submission
Consideration of the evidence
Implementation
Related guidance
Proposed date for review of guidance
Appendix A: Appraisal Committee members and NICE project team
Appendix B: Sources of evidence considered by the Committee
Appendix C: List of organisations involved in this appraisal
Background
The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of pemetrexed for the treatment of non-small-cell lung cancer and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal. The Committee has developed preliminary recommendations on the use of pemetrexed for the treatment of non-small-cell lung cancer.
This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process. This document should be read in conjunction with the manufacturer’s submission and the evidence review group report,
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.
The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the single technology appraisal process’ .
- The Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
- At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
- After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.
- Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales.
The key dates for this appraisal are:
Closing date for comments: 4 December 2006
Second Appraisal Committee meeting: 11 January 2006
Details of membership of the Appraisal Committee are given in appendix A and a list of the sources of evidence used in the preparation of this document is given in appendix B.
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.
| 1 | Appraisal Committee's preliminary recommendations |
| 1.1 | Pemetrexed is not recommended for the treatment of locally advanced or metastatic non-small-cell lung cancer. |
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| 2 | The technology |
| 2.1 | Pemetrexed (Alimta, Eli Lilly and Company) is an antifolate agent that works by disrupting folate-dependent metabolic processes essential for cancer cell replication. Pemetrexed is licensed as a monotherapy for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) after prior chemotherapy. For further information see the summary of product characteristics (SPC). |
| 2.2 | Pemetrexed is associated with suppression of bone marrow function, nausea and vomiting, fatigue and a range of other side effects. For full details of side effects and contraindications, see the SPC. |
| 2.3 | The recommended dose of pemetrexed is 500 mg/m2 body surface area. It is administered by intravenous infusion over 10 minutes on the first day of each 21-day cycle. |
| 2.4 |
The acquisition cost of pemetrexed is £800.00 for a 500-mg vial (excluding VAT; ‘British national formulary’, 51st edition). The typical cost for a course of treatment is £8000 assuming five cycles of treatment (with vial wastage). Costs may vary in different settings because of negotiated procurement discounts. |
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| 3 | The manufacturer's submission |
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The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pemetrexed and a review of this submission by the evidence review group (ERG) (appendix B). | |
| 3.1 | The manufacturer approached the decision problem by comparing pemetrexed with docetaxel and with best supportive care (BSC). The population under consideration was people with locally advanced or metastatic NSCLC who had relapsed after previous chemotherapy. The primary outcome measure outlined in the decision problem was overall survival. Secondary outcome measures included time to documented progression of disease, progression-free survival, duration of tumour response, quality of life and the incidence of adverse events. |
| 3.2 | The manufacturer’s submission presented evidence on the clinical effectiveness of pemetrexed from one open-label randomised controlled trial (RCT) that compared pemetrexed with docetaxel. Final analyses showed no significant difference in median overall survival (pemetrexed 8.3 months versus docetaxel 7.9 months, p = 0.93, hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.82 to 1.20). A hypothesis that pemetrexed was not inferior to docetaxel was also tested using two alternative methods. One test used a ‘fixed margin method’ to test whether treatment with pemetrexed achieved at least 90% of the overall survival benefit of docetaxel, and did not reach statistical significance (p = 0.226). The other test used a ‘percentage efficacy method’ to test whether pemetrexed retained at least 50% of the survival benefit of docetaxel, and incorporated data on the effectiveness of docetaxel from an RCT of docetaxel compared to best supportive care (HR 0.56, 95% CI 0.35 to 0.88). The results of this test were statistically significant and showed that pemetrexed retained 102% (95% CI 52% to 157%) of the survival benefit of docetaxel over BSC (p = 0.047). |
| 3.3 | As regards adverse effects reported in the RCT, pemetrexed was associated with fewer grade 3 and 4 haematological toxicities than docetaxel. There was statistically significantly less neutropenia (p < 0.001), febrile neutropenia (p < 0.001) and neutropenia with infection (p = 0.004) in the pemetrexed group. No statistically significant differences were found for anaemia (or number of patients receiving red blood cell transfusions or erythropoietin) or thrombocytopenia. There were no statistically significant differences for 10 of the 12 non-haematological toxicities reported, but the docetaxel group had statistically significantly more alopecia (p < 0.001) and a higher percentage of the pemetrexed group had raised levels of alanine transferase, an indicator of impaired liver function (p = 0.028). |
| 3.4 | The RCT reported no statistically significant differences in disease-specific quality of life measured using the Lung Cancer Symptom Scale, which includes six symptoms (anorexia, fatigue, cough, dyspnoea, haemoptysis and pain). |
| 3.5 | The manufacturer’s submission presented an economic analysis based on a Markov model with a 3-year time horizon. The estimates of efficacy used in the economic model were based on an indirect comparison of survival in which weighted absolute estimates of survival were pooled from single arms of different trials in published literature. The median overall survival was estimated to be 8.3 months for pemetrexed (95% CI 6.9 to 9.7) based on the results of one trial, 7.0 months for docetaxel (95% CI 5.6 to 9.9) based on the pooled results of seven trials, and 4.9 months for BSC (95% CI 4.2 to 5.5) based on the pooled results of three trials. The model predicted that the mean life years gained (in months) was 11.0 months for pemetrexed, 8.8 months for docetaxel and 7.2 months for BSC. |
| 3.6 | The base-case analysis compared pemetrexed with docetaxel and resulted in an incremental cost-effectiveness ratio (ICER) of £18,672 per additional quality-adjusted life year (QALY) gained. A comparison of pemetrexed with BSC resulted in an ICER of £16,458 per additional QALY gained. |
| 3.7 | The ERG reviewed the evidence submitted for clinical and cost effectiveness. The ERG judged that the open-label RCT of pemetrexed did not prove that pemetrexed had equivalent efficacy to docetaxel. Furthermore the manufacturer’s use of an indirect comparison to generate estimates of efficacy for its model was rejected by the ERG. The ERG noted that the manufacturer’s indirect comparison estimate of median survival with docetaxel was less than the survival estimate obtained from the head-to-head trial (7.0 compared with 7.9 months). The ERG pointed out that indirect comparison is only acceptable where direct comparison evidence is not available, and noted that the method was further flawed because it was based on an average of the absolute survival estimates from individual arms of the trials rather than a consideration of the relative treatment effects. The ERG also noted that the estimates of drug acquisition costs used needed adjustment, in particular the number of chemotherapy cycles should have reflected the number of cycles reported in the head to head trial. |
| 3.8 | The ERG considered the effect on the ICER of assuming equivalent overall survival for pemetrexed and docetaxel in place of the manufacturer’s estimates, which were based on the pooled indirect comparison and assumed a survival benefit for pemetrexed. The ERG estimated the ICER for pemetrexed versus docetaxel to be £458,333 per additional QALY gained. The ERG also noted that if their revised cost estimates were included in the analysis, the ICER for pemetrexed versus docetaxel would be £1.8 million per additional QALY gained. |
| 3.9 | The ERG also applied the modifications to the estimates of survival benefit and costs to the manufacturer’s economic analysis of pemetrexed versus BSC. The revised ICER was estimated to be £59,431 per additional QALY gained. |
| 3.10 | Full details of all the evidence are in the manufacturer’s submission and the ERG report. |
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| 4 | Consideration of the evidence |
| 4.1 | The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of pemetrexed for the treatment of NSCLC, having considered evidence (appendix B) on the nature of the condition and the value placed on the benefits of pemetrexed by people with NSCLC, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. |
| 4.2 | The Committee considered the evidence on the clinical effectiveness of pemetrexed for the treatment of NSCLC. It considered the results of the clinical trial that compared pemetrexed with docetaxel and noted that survival in the pemetrexed arm was not statistically significantly greater than in the docetaxel arm. |
| 4.3 | The Committee heard from the clinical specialists and patient experts that pemetrexed was a potential treatment for relapsed patients with NSCLC, in whom there are few treatment options. The Committee also heard that some patients may prefer pemetrexed to docetaxel because of its different side-effect profile, particularly the lower rate of alopecia. However, the Committee also heard from the clinical specialists that patients undergoing second-line chemotherapy treatment usually valued other effects of treatment more highly, in particular increased life expectancy and overall quality of life. The Committee considered that although hair loss was an important issue for some people, particularly women, the lower rate of alopecia with pemetrexed was of variable importance to either patients or clinicians and would not normally preclude consideration of a particular chemotherapy regimen. It concluded that the reduction in rates of alopecia was not sufficient reason to recommend pemetrexed as an alternative to docetaxel. . |
| 4.4 | The Committee considered the role of pemetrexed in the treatment of patients who have had an allergic reaction to docetaxel. The Committee heard from the clinical specialists that some patients experience mild allergic reactions to docetaxel (such as rash or nausea). In these circumstances it is usual to treat the reaction rather than discontinue treatment. The Committee also heard that some patients experience a severe neuropathic reaction to first-line platinum-based chemotherapy or an anaphylactic reaction (such as bronchospasm or hypotension) to docetaxel and that initiation or continuation of docetaxel second-line therapy might therefore be unsuitable for them. However the Committee noted that these types of toxicity and allergic reactions are rare and did not consider it appropriate to modify the general guidance on use of pemetrexed therapy on this basis. |
| 4.5 | The Committee considered the manufacturer’s assessment of the cost effectiveness of pemetrexed compared to docetaxel. It noted that the analysis was based on an indirect comparison of pooled absolute survival estimates from several trials and not on the results of the RCT that directly compared pemetrexed with docetaxel. The Committee noted that the analysis contradicted the result of the RCT in concluding that patients treated with pemetrexed would have a greater mean survival than patients treated with docetaxel. The Committee concluded that the survival estimates included in the manufacturer’s economic analysis were inappropriate. |
| 4.6 | The Committee considered the ERG’s critique of the economic analysis. The Committee noted that if an assumption of equivalent survival for docetaxel and pemetrexed were used in the economic analysis, the resulting ICER for pemetrexed compared to docetaxel would be over £450,000 per additional QALY gained. The Committee considered the estimates of cost included in the manufacturer’s economic analysis, particularly those relating to the number of cycles of treatment and the inclusion of non-treatment costs. It noted that if the ERG’s revised estimates of costs were included, the ICER for pemetrexed compared to docetaxel would be further increased to over £1 million per additional QALY gained. |
| 4.7 | The Committee considered the evidence on the cost effectiveness of pemetrexed compared to BSC. It noted that if the ERG’s revised estimates of costs were used in the analysis, the ICER would be over £40,000 per additional QALY gained. It also noted that if the ERG’S revised estimates of effectiveness were also included the ICER would be nearly £60,000 per additional QALY gained. The Committee concluded that this best estimate indicated that pemetrexed would not be a cost-effective use of NHS resources when compared to either docetaxel or BSC. |
| 4.8 | After considering all the evidence available, the Committee concluded that pemetrexed should not be recommended for the treatment of locally advanced or metastatic NSCLC |
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| 5 | Implementation |
| 5.1 | The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health’ issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals, normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals. |
| 5.2 | 'Healthcare Standards for Wales’ was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003, which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months. |
| 5.3 | NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [Note: tools will be available when the final guidance is issued] |
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| 6 |
Related guidance |
| 6.1 |
NICE has issued the following related clinical guideline. Lung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline no. 24 (February 2005). |
| 6.2 |
NICE is in the process of producing the following technology appraisal guidance. Pemetrexed disodium for the treatment of mesothelioma (publication date to be confirmed). Erlotinib for the treatment of non-small cell lung cancer (publication expected December 2006). |
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| 7 | Proposed date for review of guidance |
| 7.1 | The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. |
| 7.2 | It is proposed that the guidance on this technology is considered for review in December 2009. The Institute would particularly welcome comment on this proposed date. |
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Andrew Stevens
Chair, Appraisal Committee
October 2006
Appendix A. Appraisal Committee members and NICE project team |
A. Appraisal Committee members |
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The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with the chair and a vice chair. Each branch considers its own list of technologies and ongoing topics are not moved between the branches. Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal. The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website. Professor David Barnett Dr David W Black Mr Brian Buckley Professor Mike Campbell Carol Campbell Mr Peter Clarke Ms Jude Cohen Dr Christine Davey Dr Mike Davies Mr Richard Devereaux-Phillips Dr Rachel A Elliott Lynn Field Mrs Eleanor Grey Dr Dyfrig Hughes Dr Catherine Jackson Dr Peter Jackson Professor Peter Jones Damien Longson Professor Jonathan Michaels Dr Eugene Michael Gerard Milne Dr Martin J. Price Mr Miles Scott Professor Mark Sculpher Professor Andrew Stevens Dr Cathryn Patricia Thomas |
B. NICE Project Team |
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Each appraisal of a technology is assigned to one or more health technology analysts and a technology appraisal project manager within the Institute. Technical Lead, NICE project team Technical Advisor, NICE project team Chris Feinmann
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Appendix B. Sources of evidence considered by the Committee | |
| A |
The evidence review group report for this appraisal was prepared by Liverpool Reviews and Implementation Group (LRiG) Pemetrexed for the treatment of relapsed non-small cell lung cancer, Professor Adrian Bagust, Ms Angela Boland, Dr Yenal Dundar, Ms Helen Davis, Ms Rumona Dickson, Dr John Green, Mrs Juliet Hockenhill, Dr Fergus Macbeth, Ms Claire McLeod, Ms Christine Proudlove, Dr James Stevenson, Professor Tom Walley, September 2006.
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| B |
The following manufacturer/sponsor provided a submission for this appraisal. Eli Lilly and Company A The following individuals were selected from clinical specialist and patient advocate nominations from the professional/specialist and patient/carer groups. They gave their expert personal view on Pemetrexed by providing written and oral evidence to the Committee. They are invited to comment on the Appraisal Consultation Document (ACD).
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Appendix C. List of organisations involved in this appraisal | |
| The following organisations accepted the invitation to participate in this appraisal. They are also invited to comment on the ACD and consultee organisations are provided with the opportunity to appeal against the FAD: | |
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Professional/specialist and patient/carer groups:
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Commentator organisations (without the right of appeal):
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